Glibenclamide-metformin combination for the treatment of diabetes mellitus of type II

ABSTRACT

PCT No. PCT/EP96/04860 Sec. 371 Date May 13, 1998 Sec. 102(e) Date May 13, 1998 PCT Filed Nov. 7, 1996 PCT Pub. No. WO97/17975 PCT Pub. Date May 22, 1997Non-insulin dependent diabetes mellitus in cases of secondary failure is treated with a combination of glibenclamide and metformin.

This is a 371 of PCT/EP96/04860 filed Nov. 7, 1996.

The present invention relates to the use of a combination consisting ofglibenclamide and metformin in one specific ratio as medicament for thetreatment of diabetes mellitus of type II.

Non-insulin dependent diabetes of type II (NID) is known to be afrequent metabolic disease and the main cause of hyperglycemia. Inrecent years, diabetes mellitus of type II has been proved to be aheterogeneous disease, with complex, unclarified metabolic aspects,which disease is characterized by three main metabolic abnormalitiescontributing to hyperglycemia: the partial or complete decrease ininsulin secretion, the resistance of the peripheral tissues to insulinand the increased hepatic production of glucose in fasting conditions.

Diet and physical exertion are unanimously recognized to be thefoundation of the therapy of diabetes of type II: both of them lead to areduction in insulin-resistance and, in the long run, to an improvementin the pancreas secretive deficit.

However, these provisions are insufficient and a pharmacological aidwith oral hypoglycemic agents is necessary. At present, the two mainfamilies of oral hypoglycemic agents available are sulfonylureas andbiguanides.

The use of sulfonylureas and biguanides in monotherapy, in most cases,allows to obtain an effective glycometabolic control for some years, ifan appropriate diet and behavioural regimen are kept. Nevertheless, theefficacy of the therapy with oral hypoglycemic agents can decrease withtime.

After a positive starting response which can last 4-5 years, monotherapybecomes ineffective in a considerable percentage of patients. These arethe so-called "secondary failures" of the therapy with oral hypoglycemicagents. Such a failure is estimated to occur each year in 5-10% of thepatients under therapy with sulfonylureas, therefore after 10 years,only 50% of the patients still show a satisfactory response.

The secondary failure in patients under treatment with metformin appearsto have an incidence superimposable to the above mentioned one.

Recent studies show that besides a qualitative/quantitative deficiencyof insulin secretion, the combined occurrence of insulin-resistanceconditions is at the bottom of NID diabetes.

Since sulfonylureas are capable of stimulating insulin release, but arenot capable of acting on insulin resistance, and biguanides are able toact on insulin resistance, whereas they are not able to stimulateinsulin secretion, the therapeutical rationale of said studies suggestedthe use of combined formulations of medicaments capable of finding aremedy for both the deficiency in insulin secretion and theinsulin-resistance condition.

Vigneri et al. (Diabete & Metabolisme, 1991, (17), 232-234), faced theproblem of secondary failure to sulfonylurea therapy in NID diabetes.The authors proposed a combination of glibenclamide-metformin in a dailydosage of 15 mg and 1500 mg, respectively, in alternative to insulintherapy in addition to glibenclamide.

The combined therapy (sulfonylurea+biguanide) plays therefore aspecifically important therapeutical role, since it allows to obtain aneffective metabolic control in those patients with diabetes of type II,in which the therapy with only sulfonylureas or only biguanides becomesineffective with time.

Two biguanides are used in the oral therapy of diabetes of type II:phenformin and metformin. Although the former is still widely used, anumber of data in literature clearly show that metformin exerts aneffective normoglycemic action with no risk of lactic acidosis in thepatients, as it can occur in some cases when using phenformin.Therefore, it is generally accepted that metformin is the preferredbiguanide in the therapy of diabetes of type II.

The Applicant found, during clinical experiments, that the sulfonylureamaximum daily dose considered optimum for the most severe, barelycontrollable cases is 15 mg. However, such a dose has to be combinedwith a biguanide maximum daily dose of 15,00 mg in order to obtain themaximum therapeutical effect together with the reduction of untowardeffects.

At present 4 combinations are marketed which use a combination ofmetformin with glibenclamide (Table 1). In the first combination,glibenclamide dose is 2.5 mg and metformin (expressed as thehydrochloride) dose is 500 mg for each tablet, namely a weight ratio of1:200. In the other combinations, doses are respectively: 2.5 mg ofglibenclamide and 400 mg of metformin, namely a weight ratio of 1:160.

                  TABLE I    ______________________________________    Ready-to-use preparations of sulfonylurea (S) -    Metformin (M) available at present:    Name      Manufacturer                          S (dose/cp) M (dose/cp)    ______________________________________    Glucomide Lipha       Glibenclamide                                      Metformin                          (2.5 mg)    (500 mg)    Glibomet  Guidotti    Glibenclamide                                      Metformin                          (2.5 mg)    (400 mg)    Suguan M  Hoechst     Glibenclamide                                      Metformin                          (2.5 mg)    (400 mg)    Bi-Euglucon M              Boehringer M                          Glibenclamide                                      Metformin                          (2.5 mg)    (400 mg)    ______________________________________

It should be noted, however, that none of these formulations attain theoptimum therapeutical effect due to the quantitative unbalance of themedicaments in combination. In fact, using the above mentionedformulations, in order to obtain the sulfonylurea maximum dose of 15 mg,which we consider optimum for the most severe, barely controllablecases, 6 tablets of the medicament should be taken, thus receiving2400-3000 mg of metformin, which is a dose markedly higher than themaximum one we recommend (1500 mg).

Therefore, the still unsolved problem is to find a combination capableof obtaining the maximum increase in the therapeutical effect withbalanced doses of the single medicaments, thereby decreasing in paralleltheir untoward effects.

Such a research is of paramount importance, taking into account that indiabetes of type II it is often necessary to progressively increase withtime the hypoglycemic medicament doses.

The present invention solves the problem to provide medicament effectivefor the treatment of diabetes mellitus of type II in cases of secondaryfailure to a combination of glibenclamide-metformin currently used intherapy.

ABSTRACT OF THE INVENTION

Now it has been found that a combination of glibenclamide and metformin(expressed as the hydrochloride) in a 1:100 weight ratio, so as to allowa daily administration of 15 mg of glibenclamide and 1500 mg ofmetformin, is suitable to the preparation of a medicament useful for thetreatment of diabetes mellitus of type II at any time of the progressionof the disease, from its onset to the most severe cases.

Therefore, it is an object of the present invention the use of the abovementioned combination in admixture with conventional carriers andexcipients for the preparation of a medicament for the treatment ofdiabetes mellitus of type II, particularly in the cases "secondaryfailure" to a combination of glibenclamide-metformin currently used intherapy.

DETAILED DISCLOSURE OF THE INVENTION

According to a first preferred embodiment of the present invention, thecombination of the two active ingredients is used in a medicament in theform of tablets with a dosage of 5 mg of glibenclamide and 500 mg ofmetformin. This medicament is useful for the treatment of diabetesmellitus of type II.

The balance of said doses makes the therapeutical effect optimum at anytime of the progression of the disease, starting from minor cases to themost severe ones, and particularly, when it is necessary to increaseprogressively with time the doses of the two substances.

On the contrary, when combination ratios different from those of thepresent invention are used, the following cases are likely to occur:

when the ratios are lower than the recommended ones, the number ofmetabolically controlled diabetic patients will definitely be lower;

when the recommended doses are exceeded, there will be an actual risk ofuntoward effects.

Therefore, the target area of the patients responding to the therapywill increase and at the same time the onset of therapeutical risks willbe highly decreased only when the two medicaments are administered incombination at the doses present in the tablet, or at multiple andsubmultiple doses of the same.

Moreover, it has been proved that a dose increase beyond the maximumlimits herein recommended of 15 mg of glibenclamide and 1500 mg ofmetformin daily causes no further favourable therapeutical effects.

Finally, it should be stressed that the above mentioned doses cantheoretically be attained also using the two medicaments separately.However, this involves the need of taking twice as many tablets a day,with clear compliance problems, especially in the elderly patients whichrequire concomitant therapies for other pathologies which are frequentlyconnected with diabetes, such as hypertension and vascular diseases.

Said combination of dosages can be used starting from the onset of thedisease in NID diabetics since the ratio of 5 mg of glibenclamide +500mg of metformin will always be balanced, in both the multiple andsubmultiple dosages. In fact, when the tablets are subdivided, thusobtaining minor and/or fractional daily dosages, the fixed ratio, whichis the balanced one, is always maintained. Therefore, according to asecond embodiment of the present invention, the medicament is in theform of a divisible tablet containing the combination described above.

Alternatively, tablets containing fractions of the preferred dosage canbe prepared, always keeping the 1:100 ratio between the two activeprinciples.

Analogously, in the most severe cases of diabetes with metabolicdecompensation, which cannot be controlled with the commerciallyavailable combination medicaments, (so that the patients should turn toinsulin therapy), the combination of the invention allows to treat them,still and for a long time, with the oral therapy, with obvious benefitsfor the patients themselves.

In confirmation of what stated above, the study profile and the resultsof the experimentation carried out are reported in the following.

STUDY PROFILE

Sample size

About 100 diabetics of type II (non insulin-dependent) have beenstudied. The sample was calculated so that a clinically significantaverage reduction of the values of glycated hemoglobin A1c equal to orhigher than 0.6% and an average reduction of glycemia equal to or higherthan 18 mg/dl in the 16 weeks of treatment could be detected. Thestandard deviations envisaged for HbA1c and for fasting glycemia are1.46% and 44 mg/dl. The analysis makes use of a significance level of0.05 and a test power of 0.80 (two-tail test).

Description of the studied panel

98 Patients with diabetes mellitus of type II (non insulin-dependent)were studied. The average age of the subjects was 57.3±6.6 years.

The panel consisted of 45 males (46%) and 53 females (54%) ofsuperimposable age.

Starting metabolic profile

The fasting glycemia measured at examination 1 was 219±37 mg/dl (95%confidence limits: 211-226 mg/dl; 10-90° percentile: 184-272 mg/dl), 24hour glycosuria 25±36 g (95% confidence limits: 18-33 g; 10-90percentile 7-64 g), no acetonuria in all of thus patients, glycatedhemoglobin A1c 9.1±0.9% (95% confidence limits 8.9-9.2%; 10-90°percentile:8-10.1%).

                  TABLE A    ______________________________________    Metabolic profile of the subjects studied in each    centre.                                            ANOVA                                            Oneway    Centre  1        2        3      4      p =    ______________________________________    N       9        31       38     20    Fasting 219 ± 41                     211 ± 33                              221 ± 42                                     226 ± 29                                            ns    glycemia    (mg/dl)    24 hour  11 ± 14*                     25 ± 15                              37 ± 54                                     **     0.026    glycosuria    (g/24 hours)    Acetonuria            0        0        0      0      --    Glycated            8.8 + 1,1                     9.1 ± 0.7                              8.8 ± 1,0                                      9.6 ± 0.4.sup.°                                            0.002    hemoglobin    A1c (%)    ______________________________________     *p < 0.05 Centre 1 vs Centre 3     ** At the Centre 4, glycosuria was doses with a semiquantitative procedur     °p < 0.05 Centre 4 vs Centres 1, 2. 3

Evaluation of the efficacy of the treatment

The parameters the evaluation of the efficacy of the treatment is basedon are:

1. fasting glycemia;

2. post-prandial glycemia;

3. 24 hour glycosuria;

4. presence of acetone in the urines;

5. glycated hemoglobin (HbA1c).

Other important parameters evaluated during the study are:

1. body weight

2. total cholesterol plasma levels;

3. HDL cholesterol plasma levels;

4. LDL cholesterol plasma levels;

5. arterial pressure values.

Fasting glycemia

The average values of the fasting glycemia evidenced during the studyare reported in Table B.

                                      TABLE B    __________________________________________________________________________                                  Variance    Examinations             1  2  2b 3  4  5  6  analysis for repeated    Weeks    -3 0  2  4  8  12 16 measurements p <    __________________________________________________________________________                                  1 factor analysis    Whole    219                226                   194*                      192*                         192*                            186*                               184*                                  0.0001    Panel: M ± (ds)             (37)                (58)                   (52)                      (50)                         (55)                            (51)                               (53)                                  (F = 24)    Single Centres:               1 factor analysis    Centre 1 224                248                   225                      236                         232                            221                               232                                  0.426    Centre 2 214                197                   171§                      173§                         171§                            161§                               174§                                  0.0001    Centre 3 222                247                   207$                      206$                         216$                            213$                               203$                                  0.0001    Centre 4 226                220                   184*                      174*                         162*                            156*                               145*                                  0.0001    Anova    ns 0.002                   0.003                      0.003                         0.001                            0.001                               0.001    Oneway (p <)                  2 factor analysis    among centres                 0.0001    among examinations            0.0001    __________________________________________________________________________     *p < 0.001 vs Examination 1 and Examination 2     §p < 0.001 vs Examination 1. p < 0.01 vs Examination 2     #p < 0.05 vs Examination 1     $ p < 0.01 vs Examination 2

In the whole panel, the fasting glycemia underwent a significantreduction already after two weeks of treatment (p<0.001); said reductionwas maintained subsequently during all the study (16 weeks). Similarresults were obtained from the analysis carried out at the singleCentres (Centres 2-4). Only in Centre 1, no reduction in glycemia wasdetected, partly probably due to the small number (n. 9) of the studiedsubjects (Table B).

Table C reports the results of the glycemia course in subjectsstratified as a function of the Body Mass Index (BMI; normal weight:BMI<25 kg/m². n=21; overweight BMI 25-30 kg/m². n=52; obeses BMI≧30kg/m². n=259).

                                      TABLE C    __________________________________________________________________________    Fasting glycemia: changes during the study.    The subjects were stratified depending on BMI (Body Mass Index).                                  Variance    Examinations             1  2  2b 3  4  5  6  for analysis repeated    Weeks    -3 0  2  4  8  12 16 measurements p <    __________________________________________________________________________    BMI                           1 Factor analysis    <25 kg/m.sup.2             214                212                   180*                      167*                         173*                            175*                               168*                                  0.0001    25-30 kg/m.sup.2             220                223                   192                      196*                         194*                            186*                               182*                                  0.0001    ≧30 kg/m.sup.2             227                247                   208§                      208§                         207§                            196§                               205§                                  0.035    Anova    ns ns ns 0.02                         ns ns    Oneway (p <)                  2 Factor analysis    among groups                  0.0001    among examinations            0.0001    __________________________________________________________________________     *p < 0.001 vs Examination 1 and Examination 2     §p < 0.05 vs Examination 2

The effects of the treatment are clear (variance analysis for repeatedmeasurements, p<0.0001) in the subjects with normal body weight and, inthe overweight subjects (BMI 25-30 kg/m²), which are less sensitive, butstill statistically significant (p<0.035 in the obese subgroup (BMI>30kg/m²)).

Post-prandial glycemia

The mean values of the fasting glycemia evidenced during the study arereported in Table D. The post-prandial glycemia, measured at thebeginning and at the end of the study, underwent a significant reductionboth in the whole panel (318 to 267/mg/dl) and in each of the subgroupsdefined depending on the Body Mass Index.

                  TABLE D    ______________________________________    Post-prandial glycemia: changes during the study.    In the second part of the table the subjects were    stratified depending on the BMI (Body Mass Index).    ______________________________________    Examinations  2       6      Student's t test for                                 coupled data weeks (p <)                  0       16    ______________________________________    Whole        318     267     0.0001    Panel:       (64)    (79)    ______________________________________    BMI:                         Variance analysis for                                 measurements (1 factor)    <25 kg/m.sup.2                 317     252     0.0001    25-30 kg/m.sup.2                 320     263     0.0001    ≧30 kg/m.sup.2                 313     287     0.001    Anova        ns      ns    Oneway (p <)                                 2 Factor analysis    among groups                 ns    among examinations           0.0001    ______________________________________

Adverse events

The untoward effects were infrequent and slight; in practice, onlygastro-intestinal untoward effects such as nausea, abdomen pains anddiarrhoea, more or less combined together, occurred.

Conclusions about the therapeutical efficacy

In the clinical study carried out, the proposed combination(glibenclamide 5 mg - metformin 500 mg) was administered for 16 weeks topatients with diabetes of type II, in which the combined treatment withglibenclamide-metformin at the presently available dosages gave nolonger an acceptable metabolic control.

The main result from the evaluation of the efficacy consists in thesignificant decrease in the fasting glycemia (-35 mg/dl), in theglycemia 2 hours after meals (-51 mg/dl) and in the HbA1c (-0.9%).

These results are of particular value when considering that:

1. Whereas the patients with a more severe diabetic condition (so as tobe necessary the use of high dosages of glibenclamide and metformin),actually were no longer responsive to the sulfonylurea-metformincombinations commercially available and as a consequence it wasnecessary to start the subsequent therapeutical option, i.e. theaddition of insulin to the oral therapy or the complete substitution ofthe latter with insulin itself. These cases were treated successfullyand the obtained results prove that the combination glibenclamide 5mg+metformin 500 mg is an important therapeutical tool, which allows toobtain an effective control of glycid metabolism still making use of theonly hypoglycemizing oral therapy, thus obtaining a further favourableeffect on life-quality of the patients themselves.

2. On the contrary, for the less severe cases, the ratio 5 mg ofglibenclamide+500 mg of metformin, can be subdivided as desired, therebyhaving lower and/or fractional daily dosages thus allowing to treat thedisease from its onset, as the glibenclamide to metformin ratio, evenwhen fractioned, will turn out to be very well balanced.

As far as the industrial applicability aspects are concerned, themedicaments according to the invention are provided in the form ofpharmaceutical composition, which can be prepared according toconventional techniques known to those skilled in the art, for exampleas described in Remington's Pharmaceutical Sciences Handbook, Mack.Pub., N.Y., U.S.A.

Among the pharmaceutical compositions intended for the treatment ofdiabetes mellitus of type II, those which are administered orally arepreferred, such as coated or non-coated tablets, capsules, sugar-coatedpills, granulates, oral suspensions, microgranules, controlled-releasetablets.

Metformin is used preferably in the form of metformin hydrochloridesalt. Of course, it is also possible to use equivalent amounts of otherphosphate, solfite, dithionate, acetate, benzoate, citrate salts and thelike, optionally together with suitable buffers.

On the contrary, glibenclamide is an insoluble substance.

Since said compound has to be administered in comparatively high dosages(5 mg of Glibenclamide+500 mg of Metformin HCl) and for long times inorder to obtain a complete action, the oral route was considered thesimpliest administration method.

In the galenic study carried out to accomplish the most suitablepharmaceutical form, the following objectives were taken into account:

ready contact of the active ingredient in the dispersed state withgastroenteral mucosae

easiness of swallowing

posology flexibility

optimization of the technological characteristics of the granulate forthe working up with fast devices

choice of the material suitable for the preservation of the product

manufacturing process easy to carry out and economical.

Considering the high unitary dosage required, the pharmaceuticalformulation in lozenge-shaped tablets, with a central breaking division,has been chosen since it is considered the most suitable one. Such atablet can have the composition as shown in Example 1.

In fact this allows, with comparatively limited sizes, to carry suitablythe active ingredient, so as to combine a favourable working-up withoptimum biopharmaceutical and technical characteristics besides animproved swallowability.

The tablets were subjected to wet-granulation; the excipients reportedhereinbelow were selected, after a number of laboratory tests in orderto find the amount of each excipient to attain the best workabilitytogether with biopharmaceutical and technological characteristics of thetablets:

maize starch: diluent and disintegrant;

precipitated silica: it promotes the cohesion of the granulatesimproving their flowability;

microcristalline cellulose (Avicel PH 101): a diluent, which favours theformation of compact granules and therefore of more resistant tabletscontributing at the same time to disaggregation of the pharmaceuticalform, promoting the penetration of liquid inside it by capillarity;

gelatin: a binder used in solution to wet the granular mixture;

glycerin: it is used in the gelatin solution to promote wetting and as aplasticizer;

talc: a lubricant;

magnesium stearate: a solid lubricant which is effective in amountswhich do not significantly affect the disaggregation time of thetablets.

In order to improve handling and swallowing, a coating was moreoverapplied onto the tablets, which consists of a methylhydroxypropylcellulose film as a film-forming agent, titanium dioxide as an opacifierand polyethylene glycol 400 as a plasticizer. The compatibility amongthe active ingredient and the selected excipients was ascertained bypreliminary accelerated stability studies.

Finally, for the choice of the container, the physico-chemicalcharacteristics of the active ingredient and of the tablet wereconsidered in order to guarantee a safe preservation; the medicament ofthe invention showed a very good stability in an opaque blisterconsisting of PVC/PVDC and aluminium.

The manufacturing process was carried out by wet granulation both bymeans of kneading in a fast granulator and drying in air-circulationdrier, and in fluidized bed granulator-drier. In both cases, tabletswith the desired characteristics were obtained.

The following examples further illustrate the invention.

EXAMPLE 1

A coated tablet contains:

    ______________________________________    Glibenclamide        mg    5.00    Metformin hydrochloride                         mg    500.00    Maize starch         mg    57.50    Precipitate silica   mg    20.00    Microcrystalline cellulose                         mg    65.00    Gelatin              mg    40.00    Glycerin             mg    17.50    Talc                 mg    17.50    Magnesium stearate   mg    7.50    Methylhydroxypropylcellulose                         mg    12.50    Titanium dioxide     mg    6.25    Polyethylene glycol 400                         mg    1.25    Unitary theor. average weight                         mg    750.0    ______________________________________

EXAMPLE 2

Granulate sachets:

    ______________________________________    Glibenclamide:       mg    5.00    Metformin hydrochloride                         mg    500.00    Polyvinylpyrrolidone mg    22.00    Saccharose           mg    1000.00    Mannitol             mg    821.00    Sodium saccharinate  mg    10.00    Orange flavour       mg    37.00    Lemon flavour        mg    10.00    Unitary theor. average weight                         mg    2405.00    ______________________________________

EXAMPLE 3

Suspension:

    ______________________________________    Glibenclamide         g     10.100    Metformin hydrochloride                          g     0.047    Sodium carboxymethylcellulose                          g     0.079    Microcrystalline cellulose                          g     0.300    Wild black cherry essence                          g     0.089    Anise essence         g     0.050    Glycerol              g     10.000    Methyl p-hydroxybenzoate                          g     0.050    Saccharose            g     77.470    Depurated water q.s. to                          ml    100    ______________________________________

We claim:
 1. A method of treating non-insulin dependent diabetes mellitus in cases of secondary failure comprising administering to a subject a need of same a combination of glibenclamide and metformin, expressed as the hydrochloride, in a weight ratio higher than 1:100.
 2. A method of treating non-insulin dependent diabetes mellitus in cases of secondary failure comprising administering to a subject in need of same a combination of glibenclamide and metformin, expressed as the hydrochloride, in a weight ratio of 1:160 to 1:200.
 3. The method according to claim 1 or 2 wherein a daily dosage of up to 15 mg of glibenclamide and 1500 mg of metformin is administered.
 4. The method according to claim 1 or 2 wherein a unitary dose administered contains 5 mg of glibenclamide and 500 mg of metformin.
 5. The method according to claim 4 wherein the medicament is in the form of a tablet.
 6. The method according to claim 5 wherein the table its divisible.
 7. The method according to claim 1 or 2 in which a metformin salt is a hydrochloride. 